Mice and Rats as Pets

Owners of pet rodents, especially rats, will often travel long distances to see a knowledgeable veterinarian, as many clinicians are unfamiliar with their diseases. Although a great deal of information has been accumulated on wild and laboratory rodents, very little of this information pertains to pet rodents.

The prevalence and type of mouse and rat diseases seen in practice are quite different from those seen in a research setting. The diagnosis and treatment of pet mice and rats involves evaluation and care of an individual animal from a household, not the health management of rodents from a research colony. Diseases likely to be seen in practice include trauma-induced injuries, infectious diseases, and problems related to nutrition and aging. Natural infections that would be considered rare in a laboratory animal colony (eg, mycoplasmosis) are common in pet rats and mice. The most frequent problems in mice and rats are dermatopathies, respiratory infections, and neoplasia.

Male mice and rats are sexually mature at a similar age to females, but produce a small amount of sperm daily at puberty (eg, 40–50 days in a rat). It is not until 75–100 days that optimal sperm production and reserve occur in rats. While male rodents show a constant libido after sexual maturity, females are receptive to copulation only during estrus. Males cannot fertilize females until 6–8 wk after reaching puberty.

The typical lifespan is 18–24 mo in mice and 18–36 mo in rats. Restricting the number of calories, without compromising overall nutrition, increases lifespan. Obesity in pets rats and mice is common, and calorie-restricted pets live significantly longer lives.

Husbandry

The best cages are made of a material that is easy to clean and deodorize and is indestructible to rodent chewing or digging in the corners. The cage floor should be waterproof and easy to clean. Wire mesh floors are not recommended because rats and mice can trap their feet and especially hindlimbs in the openings, resulting in fractures and injuries.

Cage bedding is described based on its use (eg, contact, noncontact, and enrichment bedding) or the material from which it is made (eg, wood-based, paper-based, corn, cellulose, and vermiculite). The purpose of bedding is to keep animals dry and clean. Pet owners generally choose bedding based on cost and availability, while laboratory veterinarians choose bedding based on cost and water-holding capacity. Some pet bedding contains lemon and chlorophyll to give it a pleasant scent. This type of bedding irritates pet rodents, and the coloring agents can stain white rats or mice. Traditionally, owners prefer paper and softwood chips, such as pine or aspen, to straw because fewer bedding changes are required. Although cedar and other wood chip shavings can reduce ectoparasite problems and have a pleasant scent, such bedding is not recommended due to emission of toxic aromatic hydrocarbons that increase the incidence of cancer in animals and cause mouse and rat pup mortality.

Owners must combine frequent bedding changes with good husbandry such as regular cage cleaning, low animal density, and low environmental temperature and humidity. This will reduce the buildup of toxic or odor-causing gases such as ammonia due to bacterial breakdown of urine. Aquariums are not suitable cages for rats and mice because of inadequate air circulation and subsequent ammonia buildup. Environmental temperature and relative humidity can depend on husbandry and housing design and may differ considerably between the cage and room. Factors that contribute to variation in temperature and humidity include cage material and construction, number of animals per cage, frequency of bedding changes, and bedding type.

Size and manipulability of bedding material are the main determinants of mice and rats' preferences. Mice and rats prefer bedding consisting of large, fibrous particles. When exposed to different types of nesting materials such as paper strips; cornhusks; sawdust; and wood shavings, peelings, and chips, rats choose long strips of soft paper. Rats also select opaque or semiopaque nest boxes to transparent nest boxes. Mice show no preference between paper and wood-derived materials, but show a clear preference for materials that they can manipulate such as paper tissues; string; and wood shavings, peelings, and chips. Many mice will combine 2 preferred nesting materials to make complex nests.

In environmentally enriched cages with hollow tubes, mice have no overwhelming preference for shape, opacity, or openness of tubes and prefer to sleep in sawdust when it is available. Mice will sleep in hollow tubes only after the sawdust is removed. Then they use short, wide tubes more frequently than long or short narrow tubes.

Mice and rats are optimally maintained at a temperature of 64–79°F (18–26°C). An acceptable range of relative humidity is 30–70%. Both temperature and humidity regulation are important to prevent ringtail and exacerbation of respiratory disease. Avascular necrosis of the tail, or ringtail, occurs primarily in young rats in low-humidity environments. Excess heat and humidity cause heat stroke and indirectly cause decompensation of chronic respiratory disease, resulting in death.

Mouse and rat owners should check water bottles daily. If mice are deprived of water for only a short time, and experience dramatic fluctuations in the surrounding temperature, especially over 99°F (37°C), they die. In contrast, healthy rats tolerate water deprivation and temperature fluctuations better. They can live for up to a week without water, in temperatures of 64–79°F, although they may lose up to 65% of their body weight.

Most rodent enrichment studies focus on modifying the area inside the enclosure rather than the size of an enclosure. However, rats prefer larger cages and experimental studies suggest rats should have a larger space that allows sharing of the environment with up to 4 other rats.

The minimum recommended height of cages should take into account typical postures of a rat or mouse. This includes the animal standing fully erect on its hind legs, and vertical movements such as stretching upward and possibly climbing. Consequently, minimal cage heights of 12–15 in. (30–38 cm) for rats and 7–8 in. (18–20 cm) for mice are recommended.

Environmental enrichment is important. For example, suspended cloth hammocks are popular with rats, and suspended (plastic or stainless steel) shower-hooks fitted into one another can be used to make a swinging chain. Rats will use more enrichment devices than mice. However, they stop using the devices 3–4 days after introduction. Rotation of enrichment toys and introduction of novel devices increase use of items. Food treats are also valuable enrichment items. These can range from simple, inexpensive treats such as a daily piece of a breakfast cereal to formulated nutritious or calorie-free treats. Rats love chocolate, and it is not toxic in this species when fed in small amounts. Pet rodents accustomed to handling will eat food treats out of the owner's hand. This daily routine can enable detection of subtle changes in the pet's behavior. Sick rodents are very good at hiding signs of disease. Sick rats do not show the same interest in their daily treat, and this can alert the owner early to disease when it is still treatable.

Housing male and female rodents together will result in mating and subsequent litters. Mice and rats experience postpar-turient estrus, and fertilization can take place. However, implantation of the resulting blastocysts is delayed during lactation and occurs at weaning, ensuring that the next litter is not born until the earlier one has been weaned. Unless opposite-sex rodents housed together are separated or neutered, having a new litter every 3–5 wk is possible.

Rats and mice are not strict herbivores like rabbits, guinea pigs, or chinchillas. They are omnivores and will eat food of both plant and animal origin. In the wild, rats and mice eat a wide variety of seeds, grains, and other plant material as well as invertebrates, small vertebrates, and carrion. Their ability to scavenge partly accounts for their successful colonization of diverse geographic regions.

Specially formulated diets for laboratory rodents that come as pellets are convenient and nutritionally balanced sources of nourishment for early life and reproduction. These diets are relatively high in fat and low in fiber. When provided ad libitum, they cause pathologic obesity. Consequently, the amount of pelleted diet owners provide daily should be limited. Owners should supplement their pet's diet with feeds high in fiber such as vegetables, limited amounts of fruit, and occasional treats.

Coprophagy is a normal behavior in rats and mice. Unlike rabbits, which eat cecal feces from their anus, mice and rats eat fecal pellets on the floor of their caging. The amount of feces eaten varies based on the type of rodent, age, physiologic status (eg, in pregnancy coprophagy increases), and diet. On a nutritionally complete diet, rats eat ~10% of their feces. When rats are housed together, they ingest each other's feces. The unique odor of a colony is due to ingestion of feces and the group scent enables distinction between members and nonmembers. Mice perform coprophagy ∼6 times/day. Growing mice show vigorous coprophagia, eating 13 pellets/day. However, it gradually decreases to 2 pellets at 1.5 yr and 1.5 pellets at 2 yr of age.

Owners should house different species of rodents separately to prevent interspecies disease transmission. For example, rats carry Streptobacillus moniliformis, a cause of fatal septicemia in mice, as part of the normal nasopharyngeal bacterial flora. Rodents of the same species should be housed in such a way to protect vulnerable animals from more aggressive members of their group. This includes separating young animals from older animals. Female rodents are generally compatible when housed in the same cage, unless one female has lived much of her life alone. Male rats are generally compatible, especially if raised together. However, owners should never house strange male rats in the same cage because they will fight. Male mice generally fight if housed together, unless they are littermates raised together without females present. Male mice are best housed singly or with female mice.

Rats are social animals, and grooming is a socially affiliative behavior. Singly housed rats may develop isolated-rat stress syndrome if left alone without human contact or environmental enrichment. Isolation-reared rats will experience fighting, physical injuries, and weight loss when placed into a colony of socially experienced rats. Young rats should be housed together to develop social affiliation. Owners should be warned not to put singly housed rats together. Enrichment and human contact with pet rats increases production of growth factors and structural reorganization in areas of the brain involved in cognitive function.

Physical Examination

Observing the condition of the rodent's living quarters provides useful information. Information obtained from a physical examination is often limited because of the mouse or rat's size. The pet mouse or rat can be watched in its cage for activity, condition of grooming, and the presence of a head tilt or discharges. If dyspnea or depression is seen, extreme care should be taken when handling the animal, as it is probably very sick and could die from the stress of a physical examination.

Pet rodents that have been frequently and gently handled usually require only minimal restraint. Less cooperative patients must be more firmly restrained, and the use of a towel or even heavy gloves may be required. Weight should be recorded, as it is essential for calculating appropriate dosages of medications and provides an opportunity for gauging the rodent's temperament before the rest of the physical examination.

The head, ears, eyes, and nose should be examined for discharges and the oral cavity for dentition. Lymph nodes and glands of the head can be observed for size and palpated for consistency. Assessment of the head is probably the most time-consuming part of the examination. The abdomen can be palpated for consistency and the presence of unusual masses. Overzealous palpation can result in visceral rupture. The anogenital region should be examined for discharges and staining of the fur or skin. When a rodent is picked up, it generally urinates and defecates. A dipstick should be ready for performing an immediate urinalysis; feces can be caught in a small tube and examined later. The limb should be palpated for tenderness or fractures, with special attention given to the paws, noting the condition of the nails and the footpads.

Respirations and heart rate are difficult to measure in mice and rats because they are rapid. Signs of dyspnea may provide an indication of respiratory or cardiac issues. Some respiratory infections, such as mycoplasmosis, are clinically silent. These diseases can be better heard than seen; abnormal sounds called “snuffling” in rats and “chattering” in mice are noticeable without a stethoscope.

CRD is the best-understood multifactorial respiratory infection in rats. M pulmonis is the major component of CRD. Rats may live 2–3 yr with CRD. Clinical signs are highly variable. Initial infection commonly occurs without any clinical signs; early signs involve both the upper and lower respiratory tracts and may include snuffling, nasal discharge, polypnea, weight loss, hunched posture, ruffled coat, head tilt, and red tears. Respiratory mycoplasmosis varies greatly in disease expression because of environmental, host, and organism factors that influence the host-pathogen relationship. Examples of such factors include intracage ammonia levels; concurrent Sendai virus, coronavirus (sialodacryoadenitis virus), pneumonia virus of mice, rat respiratory virus, and/or CAR bacillus infection; the genetic susceptibility of the host; the virulence of the Mycoplasma strain; and vitamin A or E deficiency.

Standard treatment for rats is enrofloxacin (10 mg/kg, PO, bid for 7 days) in combination with doxycycline hyclate (5 mg/kg, PO, bid for 7 days). Although Mycoplasma and CAR bacillus will respond to this antibiotic therapy, the respiratory viruses will not. Antibiotic treatment does not cure CRD but may alleviate clinical signs. Despite high antibody titers to Mycoplasma and high antibiotic tissue levels, M pulmonis typically persists in affected animals. Signs of chronic infection often include middle ear infection (via the Eustachian tube), ciliostasis and subsequent buildup of lysozyme-rich inflammatory exudate in airways, and eventually bronchiectasis and bronchiolectasis from inflammatory damage to the bronchiolar membranes. In advanced cases, scattered areas of abscessation in one or both lungs may occur. Reduction of ammonia levels in cages by removal of bedding and use of clean paper daily and administration of bronchodilators and low levels of short-acting corticosteroids also sometimes help reduce clinical signs in advanced cases of CRD.

Bacterial pneumonia is nearly always caused by S pneumoniae, usually in combination with M pulmonis, Sendai virus, and/or CAR bacillus. Infection with C kutscheri also results in pneumonia but only in conjunction with debilitation or immunosuppression. C kutscheri pneumonia is rare in pet rats. Pneumonia caused by S pneumoniae can be of sudden onset. Young rats are more severely affected, and often the only sign they exhibit is sudden death. Mature rats may demonstrate dyspnea, snuffling, and abdominal breathing. A purulent exudate may be seen around the nares and on the front paws from wiping of the nostrils. A tentative diagnosis is based on the identification of numerous gram-positive diplococci on a Gram's stain of the exudate or in a sample submitted for cytologic examination. Severe bacteremia is an important consequence of advanced disease and results in multiorgan abscesses and infarction. Treatment must be aggressive, and the use of β-lactamase-resistant penicillins such as cloxacillin, oxacillin, and dicloxacillin, all of which can be administered orally, is recommended.

Ulcerative dermatitis caused by Staphylococcus aureus infection results from self-trauma associated with fur mite infestation or, more commonly, from scratching of the skin over an inflamed salivary gland. Rats have a remarkable ability to resist infection with S aureus. Treatment consists of clipping the toenails of the hindpaws, cleaning the ulcerated skin, and applying a topical antibiotic. Systemic treatment is rarely necessary.

The two most common causes of clinical respiratory disease in mice are Sendai virus and M pulmonis. Sendai virus is associated with an acute respiratory infection in which mice display chattering and mild respiratory distress. Neonates and weanlings may die. Adults generally recover within 2 mo. When the disease expression exceeds this pattern, the cause is most likely concurrent mycoplasmal infection. M pulmonis is the cause of chronic pneumonia, suppurative rhinitis, and occasionally otitis media. Chattering and dyspnea are caused by accumulations of purulent exudate in inflamed and thickened nasal passages. Survivors develop chronic bronchopneumonia and bronchiectasis and may develop pulmonary abscesses. (This seldom occurs in rats.) Antibiotic therapy may alleviate clinical signs but does not eliminate the infection.

Viral Infections

Viral diseases of mice and rats are common. However, most diseases are subclinical and are more significant in laboratory animals where they have the potential to affect research.

Sialodacryoadenitis virus, a coronavirus, causes inflammation and edema of the cervical salivary glands in rats. Owners of infected rats often describe their pets as having mumps. Sialodacryoadenitis virus infection is highly contagious. It initially causes rhinitis followed by epithelial necrosis and inflammatory swelling of the salivary and lacrimal glands. Cervical lymph nodes become enlarged. There is no treatment for this disease. Glandular healing follows within 7–10 days, and clinical signs subside within 30 days, with minimal residual lesions remaining. During acute inflammation, affected rats are at high risk of anesthesia-related mortality because of the decreased diameter of the upper respiratory tract lumen. Ocular lesions such as conjunctivitis, keratitis, corneal ulcers, synechia, and hyphema can occur secondary to lacrimal dysfunction. The eye lesions usually resolve but occasionally progress to chronic keratitis and megaglobus.

Parasitic Infections

Protozoa

Endoparasites are relatively common in mice. However, only 2 parasites regularly encountered in the digestive tract, the protozoan parasites Spironucleus muris and Giardia muris, are considered pathogenic, even though they are not associated with clinical signs in immunocompetent hosts. Diagnosis is based on the demonstration of characteristic trophozoites in wet mounts of fresh intestinal contents or feces. Treatment is the addition of metronidazole to the drinking water (0.04–0.10% for 14 days); however, this does not completely eliminate the infection.

Nematodes

Pinworms are ubiquitous and considered nonpathogenic in mice. Two are commonly encountered: Syphacia obvelata and Aspicularis tetraptera. Often, the only indication of pinworm infestation is rectal prolapse due to straining. To establish a diagnosis of S obvelata infestation, a clear cellophane tape impression of the perianal skin can be made. Adult S obvelata females deposit ova around the anus. A tetraptera does not deposit its ova in this area, and fecal smear or flotation is required to confirm a diagnosis. Ivermectin (2.0 mg/kg, PO, given twice at a 10-day interval) eliminates pinworms from mice. The recommended label dosage for mice with ectoparasites (0.2 mg/kg given twice at a 10-day interval) does not eliminate pinworms.

Mites

Most infectious causes of alopecia and dermatitis in mice are associated with fur mites. Generalized thinning of the hair, especially on difficult-to-groom areas such as the head and trunk, is seen. The coat often has a greasy appearance and, in cases of heavy infestation, noticeable pruritus and self-inflicted dermal ulceration may occur. Three mites are commonly seen: Myobia musculi, Myocoptes musculinus, and Radfordia affinis. M musculi is the most clinically significant mouse mite. Infestations are usually caused by more than one species. Mites are spread by direct contact with infected mice or infested bedding. Diagnosis is based on the identification of adult mites, nymphs, or eggs on hair shafts with the use of a hand lens or stereoscopic microscope. Adults and nymphs appear pearly white and elongate; eggs are oval and can be seen attached to the base of hairs or inside mature females. Mite infestations are treated with ivermectin (0.2 mg/kg, SC or PO, twice at 10-day intervals). Alternatively, a few drops of ivermectin solution (diluted to 1:100 in equal parts of water and propylene glycol for 3 treatments) can be placed on the mouse's head to allow spread by grooming and ingestion.

Ectoparasitic infestation is less common in rats than in mice. Occasionally, the fur mite Radfordia ensifera is seen. Although R ensifera infestation produces few ill effects, heavy infestation may lead to self-trauma and ulcerative dermatitis.

Fungal Infections

Dermatophytosis is uncommon in pet mice and rats. It is caused by Trichophyton mentagrophytes. Lesions, when present, are most common on the face, head, neck, and tail. The lesions have a ragged appearance, with patchy areas of alopecia and variable degrees of erythema and crusting. Pruritus is usually minimal to absent, and the lesions do not fluoresce under ultraviolet light. Mice are important as carriers of dermatophytes and represent an important zoonosis, especially for children with pet mice. T mentagrophytes can be isolated from the fur of clinically normal mice but is rare in rats.

Neoplasia

The most common subcutaneous tumor in the rat is fibroadenoma of the mammary glands. The distribution of the mammary tissue is extensive, and the tumors can occur anywhere from the neck to inguinal region. Tumors can reach 8–10 cm in diameter and occur in both males and females. The surgical technique for tumor removal is straightforward, and survival following mastectomy has been reported to be good if the tumor is benign. The prevalence of mammary tumors, as well as that of pituitary tumors, is significantly lower in ovariectomized rats than in sexually intact rats. However, the recurrence of fibroadenomas is common in uninvolved mammary tissue, and often several surgeries are needed.

In contrast, mammary tumors in mice are nearly always malignant and often are not amenable to surgical removal. The most common spontaneous tumors associated with the skin are mammary adenocarcinomas, followed by fibrosarcomas. The incidence of mammary tumors varies according to the mouse strain and the presence or absence of mouse mammary tumor viruses; the incidence is as high as 70% in some strains. In wild and outbred mice, the incidence of fibrosarcomas is 1–6%.

Subcutaneous tumors are nearly always malignant and often have ulcerated by the time a diagnosis is made. Tumors can be treated by surgical excision, but the chance of recurrence is high and the prognosis is poor.

Miscellaneous Disorders

Dental Overgrowth

Dental problems are common in pet mice and rats because of their continually erupting teeth. Overgrown incisors are seen most frequently in rats and mice, in contrast with molar occlusion seen in guinea pigs and chinchillas. Overgrowth is easily treated with a high-speed drill that cuts through the overgrown incisors without splitting or splintering them, leaving a clean, smooth surface. Cutting the teeth with rongeurs does not produce good longterm results. The incisor may fracture longitudinally; the fracture may reach the apex and cause the animal discomfort. Bacteria can enter the fractured tooth, track down to the apex, and cause an apical abscess. Extraction of the incisors is an alternative to trimming; however, this procedure is difficult because of the incisor's long roots.

Ringtail

Avascular necrosis of the tail, or ringtail, occurs primarily in young rats, and occasionally in young mice, kept in low-humidity environments. If ringtail is diagnosed, treatment involves amputation of the tail below the necrotic annular constriction.

Geriatric Disorders

Chronic progressive nephrosis is a common age-related disease in rats. The kidneys are enlarged, pale, and have a pitted, mottled surface that often contains pinpoint cysts. Lesions consist of a progressive glomerulosclerosis and widespread tubulointerstitial disease, primarily involving the proximal convoluted tubule. Proteinuria often is >10 mg/day. The disease occurs earlier and is of greater severity in males than in females. Dietary factors appear to play a role in the progression of renal disease. Caloric restriction, the feeding of low-protein diets (4–7%), and limiting the source of dietary protein reduce the incidence and severity of the disease. Treatment is supportive and involves feeding a low-protein diet.

Skin Disease in Mice

Most of the diseases seen in pet mice are associated with the skin and represent >25% of all cases. Behavioral disorders, husbandry-related problems, microbiologic parasitic infections, and idiopathic skin diseases are seen. Behavioral, husbandry-related and infectious causes of skin disease are relatively straightforward to diagnose and treat. However, many skin diseases characterized by chronic or ulcerated skin (often secondarily colonized by bacteria) are diagnosed as idiopathic. This group is commonly unresponsive to treatment, topical or systemic, and affected mice are often euthanized.

Barbering and fighting are consequences of the social rank of an individual mouse in a group. Barbering is a unique condition seen in group-housed mice in which the dominant mouse nibbles off the whiskers and hair around the muzzle and eyes of cagemates. There are no other lesions, and only one mouse, the dominant individual, retains all of its fur. Removal of the dominant mouse stops barbering; however, another mouse may assume the dominant role. Barbering is often seen in female mice caged together. Male mice, except littermates raised together from birth, are more likely to fight and may inflict severe bite wounds on one another, especially over the rump, tail, and shoulders.

Mechanical abrasion resulting from self-trauma on cage equipment is a form of husbandry-related alopecia. Small patches of alopecia appear on the lateral surfaces of the muzzle. They result from chafing on metal feeders, poorly constructed watering device openings, and metal cage tops. Unlike barbering, dermatitis may also be associated with alopecia. Treatment consists of replacing the poorly constructed equipment with non-abrading equipment. Individually housed mice can display aberrant stereotypic behavior such as polydipsia and bar chewing that results in mechanical abrasion and alopecia. In such cases, replacing the cage equipment does not help. Instead, environmental enrichment toys such as running wheels or hollow tubes should be provided. Nursing mice often have ventral abdominal and thoracic alopecia; this is normal and is nearly always associated with the extensive distribution of mammary glands.

Sometimes a pet mouse presents with clinical signs of mite infestation but no evidence of mites and no known history of recent exposure to other animals. Biopsy samples may be useful in these cases to distinguish active acariasis from dermal hypersensitivity to mites or other allergens such as timber chip bedding. Mus musculus dermal hypersensitivity is well described in certain inbred strains of mice and is characterized by severe pruritus, the presence of fine dandruff all over the body, and occasionally ulcerative dermatitis.

Idiopathic skin disease is characterized by ulcerative dermatitis with pruritus in mice that are negative for primary ectoparasitic, bacterial, or mycotic infections. Histopathologic examination and immuno-fluorescent microscopy of selected inbred strains of mice have revealed an underlying vasculitis attributed to immune complex deposition on dermal vessels. Dietary factors and dysregulated fatty acid metabolism have been implicated in the development of the ulcerative dermatitis in these mice. This common disease of mice of the C57BL6 strain is caused by an underlying immune-mediated vasculitis, and the severity appears to be modulated by dietary fat and vitamin E content. Topical treatment twice daily with 0.2% cyclosporine in 2% lidocaine gel supplemented with gentamicin 50 μg/mL results in either complete healing or near-complete healing of the ulcerated skin, regardless of the size of the ulceration.

Skin swellings in mice are usually tumors or abscesses. Needle biopsy often reveals the nature of the contents and allows diagnosis. Three opportunistic pathogens, Staphylococcus aureus, Pasteurella pneumotropica, and Streptococcus pyogenes, are isolated frequently and can cause abscesses in other organs. Antibiotic therapy with penicillins or cephalosporins, concurrent with drainage and debridement of the abscess, is effective.

Chromodacryorrhea in Rats

The Harderian glands of rats are located behind the eyes and secrete various porphyrins that give the tears a reddish color. Harderian gland secretion is increased in response to stress and disease; the tears dry around the eyes and external nares, resembling crusts of blood. Owners often describe it as hemorrhage from the eyes and nose of their rats. The porphyrins can be readily differentiated from blood with a Wood's lamp as they fluoresce under ultraviolet light. While chromodacryorrhea is not pathologic, it is a consequence of acute-onset stress such as that caused by pain, illness, or restraint. It is usually an indication of a chronic underlying disease.